Aminotriazole compounds

ABSTRACT

Compound of formula (I):  
                 
 
     wherein:  
     n is 0 or 1,  
     W represents —CO— or S(O) q  and q is 0, 1 or 2,  
     G represents a G 1 , G 2 , G 3  or G 4  group as defined in the description,  
     Z represents alkyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylakenyl, heteroarylalkynyl or heteroarylalkyl each optionally substituted,  
     A represents a grouping selected from -A 2 -, -A 1 -A 2 -, -A 2 -A 1 - and -A 1 -A 2 -A 1 - wherein A 1  is alkylene and A 2  represents phenylene, cycloalkylene, naphthylene or heteroarylene each optionally substituted,  
     R represents hydrogen, alkyl, aryl, heteroaryl, arylalkyl arylalkenyl, arylalkynyl, heteroarylakenyl, heteroarylalkynyl or heteroarylalkyl each optionally substituted,  
     R 1  represents alkyl, aryl, heteroaryle, arylalkyl arylalkenyl, arylalkynyl, heteroarylakenyl, heteroarylalkynyl or heteroarylalkyl each optionally substituted.  
     Medicinal products containing the same are useful as Neuropeptide Y receptor ligand.

SUMMARY OF THE INVENTION

[0001] The compounds of the present invention have a novel structurecharacterised by the combination of an aminotriazole group, a hydrazidestructure and an aromatic-type spacer. The compounds are used in thetreatment of pathologies associated with the neuropeptide Y (NPY).

DESCRIPTION OF THE PRIOR ART

[0002] Various NPY receptor ligands have been described recently. By wayof example, there may be mentioned cyclic peptide compounds (WO9400486), amino acid compounds of arginine (WO 9417035) or non-peptidecompounds (WO 9827063).

BACKGROUND OF THE INVENTION

[0003] The Neuropeptide Y (NPY) is a peptide of 36 amino acids, relatedto the peptide YY (PYY) and to pancreatic polypeptides (PP). Originallyisolated from pig brain (Proc. Natl. Acad. Sci., 1982, 79, 5485), NPY iswidely distributed in mammals at the level of the central and peripheralnervous systems. This neurotransmitter is present in high concentrationsin nerve fibres of the brain, but also of the heart, the sympatheticganglia, blood vessels and smooth muscles of the vas deferens and of thegastrointestinal tract. It is responsible for various physiologicaleffects which are exerted via the intermediary of specific receptors(Y). The latter form a heterogeneous group, 6 sub-types of which havebeen identified to date: Y₁ to Y₆ (Pharmacological Reviews, 1998, 50,143). NPY is involved in eating behaviour by strongly stimulating foodintake (Proc. Natl. Acad. Sci., 1985, 82, 3940), or by exerting aregulatory role on the HPA (hypothalamic-pituitary-adrenal) axis (J. ofNeuroendocrinol., 1995, 7, 273). It also exhibits anxiolytic andsedative properties (Neuropsychopharmacology, 1993, 8, 357), a strongvasoconstrictive ability (Eur. J. Pharmacol., 1984, 85, 519) whichinduces an increase in blood pressure, and also has an effect on thecircadian rhythm (Neuroscience and Biobehavioral Reviews, 1995, 19,349).

[0004] In addition to the fact that the compounds of the invention arenew, they have demonstrated an in vivo inhibitory action on food intakeand weight gain. That effect is exerted via the intermediary of bindingto the NPY receptors. It will thus be possible to use the compounds ofthe invention in the treatment of pathologies in which an NPY receptorligand is necessary, especially in the treatment of pathologiesassociated with eating behaviour disorders or energy balance disorders,such as diabetes, obesity, bulimia, anorexia nervosa, and also in thetreatment of arterial hypertension, anxiety, depression, epilepsy,sexual dysfunctions and sleep disorders.

DETAILED DESCRIPTION OF THE INVENTION

[0005] The present invention relates especially to compounds of formula(I):

[0006] wherein:

[0007] n is 0 or 1,

[0008] W represents a —CO— group or an S(O)_(q) group wherein q is 0, 1or 2,

[0009] the grouping

[0010]  represents a group selected from:

[0011] Z represents an alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted arylalkyl, optionallysubstituted arylalkenyl, optionally substituted arylalkynyl, optionallysubstituted heteroarylalkenyl, optionally substituted heteroarylalkynylor optionally substituted heteroarylalkyl group,

[0012] A represents a grouping selected from -A₂-, -A₁-A₂-, -A₂-A₁- and-A₁-A₂-A₁- wherein A₁ is an alkylene group and A₂ represents anoptionally substituted phenylene, optionally substituted naphthylene,cycloalkylene, or optionally substituted heteroarylene group,

[0013] R represents a hydrogen atom, or an alkyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutedarylalkyl, optionally substituted arylalkenyl, optionally substitutedarylalkynyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl or optionally substituted heteroarylalkylgroup,

[0014] R₁ represents a n alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted arylalkyl, optionallysubstituted arylalkenyl, optionally substituted arylalkynyl, optionallysubstituted heteroarylalkenyl, optionally substituted heteroarylalkynylor optionally substituted heteroarylalkyl group,

[0015] their enantiomers, diastereoisomers, and addition salts thereofwith a pharmaceutically acceptable acid or base,

[0016] it being understood that

[0017] the term “alkyl” denotes a linear or branched group having from 1to 6 carbon atoms,

[0018] the term “alkylene” denotes a linear or branched bivalent radicalcontaining from 1 to 6 carbon atoms,

[0019] the term alkenyl denotes a linear or branched group having from 2to 6 carbon atoms and from 1 to 3 double bond,

[0020] the term alkynyl denotes a linear or branched group having from 2to 6 carbon atoms and from 1 to 3 triple bond,

[0021] the term “aryl” denotes a phenyl, naphthyl, biphenyl,dihydronaphthyl or tetrahydronaphthyl group,

[0022] the term “heteroaryl” denotes an unsaturated or partiallyunsaturated mono- or bi-cyclic group having from 5 to 11 ring members,containing from 1 to 4 hetero atoms selected from nitrogen, oxygen andsulphur,

[0023] the terms “phenylene” and “naphthylene” denote bivalent phenyland naphthyl radicals, respectively,

[0024] the term cycloalkylene denotes a bivalent saturated cyclicradical having from 3 to 8 carbon atoms,

[0025] the term “heteroarylene” denotes a bivalent heteroaryl radical asdefined hereinbefore,

[0026] the expression “optionally substituted” applied to the terms“aryl”, “arylalkyl”, “heteroaryl” or “heteroarylalkyl” means that thosegroups are substituted on their cyclic moiety by from 1 to 5 identicalor different substituents selected from linear or branched (C₁-C₆)alkyl,linear or branched (C₁-C₆)alkoxy, halogen, hydroxy, linear or branchedperhalo-(C₁-C₆)alkyl, nitro, amino (optionally substituted by one or twolinear or branched (C₁-C₆)alkyl groups), linear or branched (C₁-C₆)acyl,aminocarbonyl (optionally substituted on the nitrogen atom by one or twolinear or branched (C₁-C₆)alkyl groups), linear or branched(C₁-C₆)acylamino, linear or branched (C₁-C₆)alkoxycarbonyl, formyl,carboxy, sulpho, nitrile, linear or branched (C₁-C₆)aminoalkyl(optionally substituted on the nitrogen atom by one or two linear orbranched (C₁-C₆)alkyl group), linear or branched (C₁-C₆)thioalkyl(optionally substituted on the sulfur atom by a linear or branched(C₁-C₆)alkyl group), or linear or branched (C₁-C₆)hydroxyalkyl(optionally substituted on the oxygen atom by a linear or branched(C₁-C₆)alkyl group),

[0027] the expression “optionally substituted” applied to the terms“phenylene”, “naphthylene” or “heteroarylene” means that those groupsare substituted by from one to three identical or different groupsselected from linear or branched (C₁-C₆)alkyl, linear or branched(C₁-C₆)alkoxy, halogen, hydroxy, linear or branchedperhalo-(C₁-C₆)alkyl, nitro, amino (optionally substituted by one or twolinear or branched (C₁-C₆)alkyl groups), linear or branched (C₁-C₆)acyl,formyl, carboxy, linear or branched (C₁-C₆)alkoxycarbonyl, aminocarbonyl(optionally substituted on the nitrogen atom by one or two linear orbranched (C₁-C₆)alkyl groups), linear or branched (C₁-C₆)acylamino andnitrile.

[0028] Among the heteroaryl groups preference is given to the pyridyl,furyl, thienyl and indolyl groups.

[0029] Among the heteroarylene groups preference is given to thepyridinylene and pyrazinylene groups.

[0030] Among the pharmaceutically acceptable acids there may bementioned by way of non-limiting example hydrochloric acid, hydrobromicacid, sulphuric acid, phosphonic acid, acetic acid, trifluoroaceticacid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaricacid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbicacid, oxalic acid, methane-sulphonic acid, camphoric acid, etc.

[0031] Among the pharmaceutically acceptable bases there may bementioned by way of non-limiting example sodium hydroxide, potassiumhydroxide, triethylamine, tert-butylamine, etc.

[0032] An advantageous aspect of the invention relates to compounds offormula (I) wherein n is 1.

[0033] Another advantageous aspect of the invention relates to compoundsof formula (I) wherein n is 0.

[0034] Preferred compounds of the invention are those wherein Wrepresents an SO₂ group.

[0035] Preferred compounds of the invention are those wherein thegrouping

[0036] represents a group selected from:

[0037] Other preferred compounds of the invention are those wherein thegrouping

[0038] represents a group selected from:

[0039] In preferred compounds of formula (I), A represents a groupingA₂, A₂ being more especially a phenylene, pyridinylene or pyrazinylenegroup.

[0040] In other preferred compounds of formula (I), A represents agrouping -A₁-A₂- or -A₂-A₁-, A₂ being more especially a phenylene,pyridinylene or pyrazinylene group.

[0041] In the compounds of formula (I), R₁ preferably represents anoptionally substituted aryl group.

[0042] In the compounds of formula (I), R will advantageously beselected from hydrogen, and an optionally substituted aryl group (moreespecially phenyl), and an optionally substituted heteroaryl group (moreespecially pyridinyl, furyl or thienyl).

[0043] An advantageous aspect of the invention relates to compounds offormula (I) wherein Z represents a group selected from alkyl, optionallysubstituted aryl and optionally substituted heteroaryl group.

[0044] The present invention relates especially advantageously tocompounds of formula (I) wherein n is 1, W represents an SO₂ group, Arepresents a group selected from phenylene, pyridinylene andpyrazinylene, R₁ represents an optionally substituted aryl group, R isselected from a hydrogen atom, an optionally substituted aryl group andan optionally substituted heteroaryl group, and Z represents an alkyl,an optionally substituted aryl group or an optionally substitutedheteroaryl group.

[0045] The preferred aryl group of the invention is the phenyl group.

[0046] The invention relates most especially to the following compounds:

[0047]N′-[4-({5-phenyl-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]benzenesulphonohydrazide

[0048]4-methoxy-N′-[4-({5-phenyl-1-[3-trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]BENZENESULPHONOHYDRAZIDE

[0049]N′-{4-[(5-phenyl-1H-1,2,4-triazol-3-yl)amino]benzoyl}benzenesulphonohydrazide

[0050]N′-(4-{[5-phenyl-1-(2-pyridyl)-1H-1,2,4-triazol-3-yl]amino}benzoyl)benzenesulphonohydrazide

[0051]N′-[4-({5-oxo-1-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1H-1,2,4-triazol-3-yl}amino)benzoyl}benzenesulphonohydrazide

[0052]N′-(4-{[5-oxo-1-(2-pyridyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl]amino}benzoyl)benzenesulphonohydrazide

[0053]N′-[(6-{[5-oxo-1-(2-pyridinyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl]amino}-3-pyridinyl)carbonyl]benzenesulphonohydrazide.

[0054] The present invention relates also to a process for thepreparation of compounds of formula (I), characterised in that there isused as starting material a compound of formula (II):

[0055] wherein A is as defined for formula (I) and P represents aprotecting group for the amine function,

[0056] which is reacted in the presence of a coupling agent with acompound of formula (III):

NH₂—(NH)_(n)—W-Z  (III)

[0057]  wherein n, W and Z are as defined for formula (I),

[0058] to yield, after deprotection of the amine function by removal ofthe P group, a compound of formula (IV):

[0059]  wherein n, A, W and Z are as defined hereinbefore,

[0060] which compound (IV) is then condensed in a basic medium with anisothiocyanate of formula (V):

[0061]  wherein R′₁ is as defined for R₁ in formula (I) or represents alinear or branched (C₁-C₆)alkoxy group,

[0062] to yield a compound of formula (VI):

[0063]  wherein n, R′₁, A, W and Z are as defined hereinbefore,

[0064] which compound of formula (VI) is:

[0065] either, when R′₁ represents a linear or branched (C₁-C₆)alkoxygroup, condensed in the presence of a coupling agent with a hydrazine offormula R—NH—NH₂, wherein R is as defined for formula (I), to yield acompound of formula (VII/a):

[0066]  wherein R, A, n, W and Z are as defined hereinbefore, and R′₁represents a linear or branched (C₁-C₆)alkoxy group,

[0067] which compound (VII/a) cyclises, spontaneously or after treatmentin an acid medium, depending upon the nature of the R group, to yield amixture of the two compounds of formulae (I/a) and (I/b):

[0068]  particular cases of the compounds of formula (I) wherein R, A,n, W and Z are as defined hereinbefore,

[0069] which compounds (I/a) and (I/b) may be separated according toconventional separation techniques,

[0070] or, when R′₁ represents an R₁ group as defined for formula (I),condensed in the presence of a coupling agent with a hydrazine offormula R—NH—NH₂, wherein R is as defined for formula (I), to yield acompound of formula (VII/b):

[0071]  wherein R₁, R, A, n, W and Z are as defined hereinbefore,

[0072] which compound (VII/b) is subjected to a cyclisation reactionfollowed by dehydration, spontaneously or after treatment in an acidmedium, depending upon the nature of the R group, to yield a mixture ofthe two compounds of formulae (I/c) and (I/d):

[0073]  particular cases of the compounds of formula (I) wherein R₁, R,A, n, W and Z are as defined hereinbefore,

[0074] which compounds (I/c) and (I/d) may be separated according toconventional separation techniques,

[0075] which compounds (I/a), (I/b), (I/c) and (I/d) constitute thetotality of the compounds of formula (I),

[0076] are separated, where appropriate, into their enantiomers and/ordiastereoisomers according to a conventional separation technique,

[0077] are converted, if desired, into addition salts thereof with apharmaceutically acceptable acid or base.

[0078] The present invention relates also to pharmaceutical compositionscomprising as active ingredient at least one compound of formula (I), onits own or in combination with one or more inert, non-toxic,pharmaceutically acceptable excipients or carriers.

[0079] Among the pharmaceutical compositions according to the inventionthere may be mentioned more especially those that are suitable for oral,parenteral, nasal or transdermal administration, tablets or dragées,sublingual tablets, gelatin capsules, lozenges, suppositories, creams,ointments, dermal gels, etc.

[0080] The useful dosage varies according to the age and weight of thepatient, the nature and severity of the disorder and the route ofadministration, which may be oral, nasal, rectal or parenteral. The unitdose generally ranges from 0.05 to 500 mg for a treatment in from 1 to 3administrations per 24 hours.

[0081] The following Examples illustrate the invention and do not limitit in any way. The structures of the compounds described were confirmedby the usual spectroscopic techniques.

[0082] The starting materials used are known products or are preparedaccording to known procedures.

EXAMPLE 1N′-[4-({5-Phenyl-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]BENZENESULPHONOHYDRAZIDEStep a: Tert-butyl4-{[2-(phenylsulphonyl)hydrazino]carbonyl}phenylcarbamate

[0083] 12.1 mmol (1.65 g) of 1-hydroxy-7-azabenzotriazole and 18 mmol(3.45 g) of EDCI are added in succession to a solution of 12 mmol (2.85g) of 4-[(tert-butoxycarbonyl)amino]benzoic acid in 20 ml ofdimethylformamide. The reaction mixture is stirred at room temperaturefor one hour, and 18 mmol (3.1 g) of benzenesulphonohydrazide are added.After stirring for eight hours at room temperature, the reaction mixtureis poured into 100 ml of a 10% hydrochloric acid solution and extractedfour times with 50 ml of ethyl acetate. The organic phase is washedtwice with 50 ml of water and then three times with an aqueous saturatedsodium hydrogen carbonate solution and once with 50 ml of an aqueoussaturated sodium chloride solution. After drying over magnesiumsulphate, filtration and concentration, the expected product isobtained.

Step b: N′-(4-(Aminobenzoyl)benzenesulphonohydrazide Hydrochloride

[0084] The compound described in the preceding Step is dissolved in 40ml of 4M hydrochloric acid in dioxane. After stirring overnight at roomtemperature, the solvent is removed by evaporation at room temperature.The residue is suspended in 300 ml of ether and filtered. The resultingsolid is washed 4 times with 30 ml of ether and then dried under reducedpressure to yield the expected product.

Step c:N-Benzoyl-N′-(4-{[2-phenylsulphonyl)hydrazino]carbonyl}phenyl)thiourea

[0085] 11.1 mmol (0.66 ml) of diisopropylethylamine are added to asuspension of 11.1 mmol (3.65 g) of the compound described in thepreceding Step in 20 ml of acetonitrile. After dissolution, 13.9 mmol(1.86 ml) of benzoyl isothiocyanate are added. The reaction mixture isstirred for 8 hours at room temperature. The precipitate that forms isfiltered off and washed twice with 5 ml of acetonitrile and 4 times with25 ml of ether to yield, after drying, the expected product.

Step d:N′-[4-({5-Phenyl-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]BENZENESULPHONOHYDRAZIDE

[0086] 3.4 mmol (0.528 ml) of 3-(trifluoromethyl)phenylhydrazine and6.16 mmol (1.41 g) of EDCI are added to a solution of 3.08 mmol (1.4 g)of the compound described in the preceding Step in 5 ml ofdimethylformamide. The reaction mixture is stirred at room temperatureovernight. The mixture is poured into 10 ml of aqueous 10% HCl and thenextracted 3 times with 100 ml of ethyl acetate. The organic phases arecombined and washed once with 20 ml of water, twice with 20 ml of anaqueous saturated sodium hydrogen carbonate solution and once with anaqueous saturated sodium chloride solution. The organic phase is driedover magnesium sulphate, filtered and evaporated.

[0087] The resulting product is purified by chromatography over silicagel using a dichloromethane/ethyl acetate mixture, 75/25, as eluant toyield the title product.

[0088] Mass spectrum: ESI-MS: MH⁺=579

[0089] The compounds of Examples 2 to 25 are obtained according to theprocess described in Example 1, using the appropriatesulphonohydrazides, isothiocyanates and hydrazines in Steps a, c and d,respectively.

EXAMPLE 2N′-[4-({5-[2-Chlorophenyl]-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]benzenesulphonohydrazide

[0090] Mass spectrum: ESI-MS: MH⁺=613

EXAMPLE 3N′-[4-({5-[2-Chlorophenyl]-1-phenyl-1H-1,2,4-triazol-3-yl}amino)benzoyl]benzenesulphonohydrazide

[0091] Mass spectrum: ESI-MS: MH⁺=545

EXAMPLE 4N′-{4-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]benzoyl}-4-methoxybenzenesulphonohydrazideEXAMPLE 5N′-(4-{[1-(4-Fluorophenyl)-5-phenyl-1H-1,2,4-triazol-3-yl]amino}benzoyl)-4-methoxybenzenesulphonohydrazideEXAMPLE 64-Methoxy-N′-[4-({5-phenyl-1-[3-trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]benzenesulphonohydrazide

[0092] Mass spectrum: ESI-MS: MH⁺=609

EXAMPLE 7N′-(4-{[1-(4-Fluorophenyl)-5-phenyl-1H-1,2,4-triazol-3-yl]amino}benzoyl)-4-methoxybenzenesulphonohydrazideEXAMPLE 8N′-{4-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]benzoyl}benzenesulphonohydrazideEXAMPLE 9N′-[4-({5-[4-Chlorophenyl]-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]benzenesulphonohydrazideEXAMPLE 10N′-(4-{[5-(4-Chlorophenyl)-1-phenyl-1H-1,2,4-triazol-3-yl]amino}benzoyl)benzenesulphonohydrazide

[0093] Mass spectrum: ESI-MS: MH⁺=546

EXAMPLE 11N′-(4-{[5-(4-Chlorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazol-3-yl]amino}benzoyl)benzenesulphonohydrazide

[0094] Mass spectrum: ESI-MS: MH⁺=564

EXAMPLE 12N′-[4-({5-[4-Methoxyphenyl]-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]benzenesulphonohydrazide

[0095] Mass spectrum: ESI-MS: MH⁺=609

EXAMPLE 13N′-(4-{[5-(4-Methoxyphenyl)-1-phenyl-1H-1,2,4-triazol-3-yl]amino}benzoyl)benzenesulphonohydrazide

[0096] Mass spectrum: ESI-MS: MH⁺=541

EXAMPLE 14N′-(4-{[1-(4-Fluorophenyl)-5-(4-methoxyphenyl)-1H-1,2,4-triazol-3-yl]amino}benzoyl)benzenesulphonohydrazide

[0097] Mass spectrum: ESI-MS: MH⁺=559

EXAMPLE 15N′-{4-[(1-Benzyl-5-phenyl-1H-1,2,4-triazol-3-yl)amino]benzoyl}benzenesulphonohydrazide

[0098] Mass spectrum: ESI-MS: MH⁺=525

EXAMPLE 16N′-{4-[(5-Phenyl-1H-1,2,4-triazol-3-yl)amino]benzoyl}benzenesulphonohydrazide

[0099] Mass spectrum: ESI-MS: MH⁺=435

EXAMPLE 17N′-(4-{[5-Phenyl-1-(2-pyridyl)-1H-1,2,4-triazol-3-yl]amino}benzoyl)benzenesulphonohydrazide

[0100] Mass spectrum: ESI-MS: MH⁺=512

EXAMPLE 18N′-[4-({5-Phenyl-1-[4-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]BENZENESULPHONOHYDRAZIDE

[0101] Mass spectrum: ESI-MS: MH⁺=579

EXAMPLE 19N′-[4-({5-Phenyl-1-[2-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]BENZENESULPHONOHYDRAZIDEEXAMPLE 204-Methyl-N′-[4-({5-phenyl-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]benzenesulphonohydrazide

[0102] Mass spectrum: ESI-MS: MH⁺=593

EXAMPLE 21N′-[4-({5-Phenyl-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]methanesulphonohydrazide

[0103] Mass spectrum: ESI-MS: MH⁺=517

EXAMPLE 222,4,6-Trichloro-N′-[4-({5-phenyl-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]benzenesulphonohydrazideEXAMPLE 232,4,6-Trimethyl-N′-[4-({5-phenyl-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]benzenesulphonohydrazide

[0104] Mass spectrum: ESI-MS: MH⁺=621

EXAMPLE 245-(Dimethylamino)-N′-[4-({5-phenyl-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]-1-naphthalenesulphonohydrazide

[0105] Mass spectrum: ESI-MS: MH⁺=672

EXAMPLE 25N′-{4-[(1-Benzyl-5-phenyl-1H-1,2,4-triazol-3-yl)amino]benzoyl}-4-methoxysulphonohydrazide

[0106] Mass spectrum: ESI-MS: MH⁺=555

EXAMPLE 26N-[4-({5-Phenyl-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]benzenesulphonamide

[0107] The expected product is obtained by using the process describedin Example 1, in Step a replacing benzenesulphonohydrazide bybenzenesulphonamide.

[0108] Mass spectrum: ESI-MS: MH⁺=564

[0109] The compounds of Examples 27 and 28 are obtained in the samemanner as for Example 26, using the appropriate isothiocyanate andhydrazine in Steps c and d, respectively.

EXAMPLE 27N-{4-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]benzoyl}benzenesulphonamide

[0110] Mass spectrum: ESI-MS: MH⁺=496

EXAMPLE 28N-(4-{[1-(4-Fluorophenyl)-5-phenyl-1H-1,2,4-triazol-3-yl]amino}benzoyl)benzenesulphonamideEXAMPLE 29N′-[4-({5-Oxo-1-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1H-1,2,4-triazol-3-yl}amino)benzoyl}benzenesulphonohydrazideStep a: Ethyl(4-{[2-(phenylsulphonyl)hydrazino]carbonyl}anilino)carbothioylcarbamate

[0111] The expected product is obtained according to the processdescribed in Example 1, Step c, replacing benzoyl isothiocyanate byethyl thioxocarbamate.

Step b:N′-[4-({5-Oxo-1-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1H-1,2,4-triazol-3-yl}amino)benzoyl}benzenesulphonohydrazide

[0112] 1.065 mmol (0.139 ml) of 3-(trifluoromethyl)phenylhydrazine and1.42 mmol (0.272 g) of EDCI are added to a solution of 0.71 mmol (0.3 g)of the compound described in the preceding Step in 3 ml ofdimethylformamide. The reaction mixture is stirred at room temperatureovernight. The mixture is poured into 5 ml of aqueous 10% HCl and thenextracted 3 times with 5 ml of ethyl acetate. The organic phases arecombined and washed once with 5 ml of water. The organic phase is driedover magnesium sulphate, filtered and evaporated. The residue is takenup in a 10% trifluoroacetic acid solution in dioxane and heated at 50°C. overnight. The reaction mixture is evaporated and the precipitatethat forms in the course of the evaporation is washed with 2 ml ofacetonitrile and twice with 5 ml of ether and then dried in vacuo toyield the title product.

[0113] Mass spectrum: ESI-MS: MH⁺=519

[0114] The compounds of Examples 30 to 39 are obtained according to theprocess described in Example 29 using the appropriate sulphonohydrazidesand hydrazines.

EXAMPLE 30N′-{4-[(5-Oxo-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)amino]benzoyl}benzenesulphonohydrazide

[0115] Mass spectrum: ESI-MS: MM⁺=451

EXAMPLE 31N′-(4-{[1-(4-Fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]amino}benzoyl)benzenesulphonohydrazide

[0116] Mass spectrum: ESI-MS: MH⁺=469

EXAMPLE 32N′-(4-{[5-Oxo-1-(2-pyridyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl]amino}benzoyl)benzenesulphonohydrazide

[0117] Mass spectrum: ESI-MS: MH⁺=452

EXAMPLE 33N′-{4-[(1-Benzyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)amino]benzoyl}benzenesulphonohydrazideEXAMPLE 344-Methyl-N′-[4-({5-oxo-1-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1H-1,2,4-triazol-3-yl}amino)benzoyl]benzenesulphonohydrazide

[0118] Mass spectrum: ESI-MS: MH⁺=533

EXAMPLE 354-Methoxy-N′-[4-({5-oxo-1-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1H-1,2,4-triazol-3-yl}amino)benzoyl]benzenesulphonohydrazide

[0119] Mass spectrum: ESI-MS: MH⁺=549

EXAMPLE 364-Methoxy-N′-{4-[(5-oxo-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)amino]benzoyl}benzenesulphonohydrazideEXAMPLE 37N′-(4-{[1-(4-Fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]amino}benzoyl)-4-methoxybenzenesulphonohydrazideEXAMPLE 38N′-{4-[(1-Benzyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)amino]benzoyl}-4-methoxybenzenesulphonohydrazideEXAMPLE 39N′-Benzoyl-4-({5-phenyl-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzohydrazide

[0120] The expected product is obtained according to the processdescribed in Example 1, in Step a replacing benzenesulphonohydrazide bybenzohydrazide.

[0121] Mass spectrum: ESI-MS: MH⁺=543

[0122] The compounds of Examples 40 to 45 are obtained in the samemanner as for Example 39, replacing sulphonohydrazide by thecorresponding hydrazide and using the appropriate isothiocyanates andhydrazines.

EXAMPLE 40N′-Benzoyl-4-[(1,5-diphenyl-1H-1,2,4-triazol-3-yl)amino]benzohydrazide

[0123] Mass spectrum: ESI-MS: MH⁺=475

EXAMPLE 41N′-Benzoyl-4-{[1-(4-fluorophenyl)-5-phenyl-1H-1,2,4-triazol-3-yl]amino}benzohydrazide

[0124] Mass spectrum: ESI-MS: MH⁺=493

EXAMPLE 42N′-Benzoyl-4-{[5-phenyl-1-(2-pyridyl)-1H-1,2,4-triazol-3-yl]amino}benzohydrazide

[0125] Mass spectrum: ESI-MS: MH⁺=476

EXAMPLE 43N′-Benzoyl-4-({1-[3,5-bis(trifluoromethyl)phenyl]-5-phenyl-1H-1,2,4-triazol-3-yl}amino)benzohydrazide

[0126] Mass spectrum: ESI-MS: MH⁺=611

EXAMPLE 444-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]-N′-(1-naphthoyl)benzohydrazide

[0127] Mass spectrum: ESI-MS: MH⁺=525

EXAMPLE 454-{[1-(4-Fluorophenyl)-5-phenyl-1H-1,2,4-triazol-3-yl]amino}-N′-(1-naphthoyl)benzohydrazide

[0128] Mass spectrum: ESI-MS: MH⁺=543

[0129] The compounds of Examples 46 to 48 are obtained according to theprocess described in Example 1, using the appropriatesulphonohydrazides, isothiocyanates and hydrazines in Steps a, c and d,respectively.

EXAMPLE 464-Methyl-N′-{4-[(5-phenyl)-1H-1,2,4-triazol-3-yl)amino]benzoyl}benzenesulphonohydrazide

[0130] Mass spectrum: ESI-MS: MH⁺=449

EXAMPLE 47N′-{4-[(5-Phenyl)-1H-1,2,4-triazol-3-yl)amino]benzoyl}methanesulphonohydrazide

[0131] Mass spectrum: ESI-MS: MH⁺=373

EXAMPLE 484-Methoxy-N′-{4-[(5-phenyl-1H-1,2,4-triazol-3-yl)amino]benzoyl}benzenesulphonohydrazide

[0132] The compounds of Examples 49 to 60 are obtained according to theprocess described in Example 1, using the appropriatesulphonohydrazides, isothiocyanates and hydrazines in Steps a, c and d,respectively, and in Step a replacing4-[(tert-butoxycarbonyl)amino]benzoic acid by3-[(tert-butoxycarbonyl)amino]benzoic acid.

EXAMPLE 49N′-[3-({5-Phenyl-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]benzenesulphonohydrazide

[0133] Mass spectrum: ESI-MS: MH⁺=579

EXAMPLE 50N′-{3-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]benzoyl}benzenesulphonohydrazide

[0134] Mass spectrum: ESI-MS: MH⁺=511

EXAMPLE 51N′-(3-{[5-Phenyl-1-(2-pyridinyl)-1H-1,2,4-triazol-3-yl]amino}benzoyl)benzenesulphonohydrazide

[0135] Mass spectrum: ESI-MS: MH⁺=512

EXAMPLE 52N′-(3-{[5-(2-Chlorophenyl)-1-phenyl-1H-1,2,4-triazol-3-yl]amino}benzoyl)benzenesulphonohydrazide

[0136] Mass spectrum: ESI-MS: MH⁺=546

EXAMPLE 53N′-(3-{[5-(2-Chlorophenyl)-1-(2-pyridinyl)-1H-1,2,4-triazol-3-yl]amino}benzoyl)benzenesulphonohydrazide

[0137] Mass spectrum: ESI-MS: MH⁺=547

EXAMPLE 544-Methoxy-N′-[3-({5-phenyl-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]benzenesulphonohydrazide

[0138] Mass spectrum: ESI-MS: MH⁺=609

EXAMPLE 55N′-{3-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]benzoyl}-4-methoxybenzenesulphonohydrazide

[0139] Mass spectrum: ESI-MS: MH⁺=541

EXAMPLE 564-Methoxy-N′-(3-{[5-phenyl-1-(2-pyridinyl)-1H-1,2,4-triazol-3-yl]amino}benzoyl)benzenesulphonohydrazide

[0140] Mass spectrum: ESI-MS: MH⁺=542

EXAMPLE 57N′-[3-({5-(2-Chlorophenyl)-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]-4-methoxybenzenesulphonohydrazide

[0141] Mass spectrum: ESI-MS: MH⁺=644

EXAMPLE 58N′-(3-{[5-(2-Chlorophenyl)-1-phenyl-1H-1,2,4-triazol-3-yl]amino}benzoyl)-4-methoxybenzenesulphonohydrazide

[0142] Mass spectrum: ESI-MS: MH⁺=576

EXAMPLE 59N′-(3-{[5-(2-Chlorophenyl)-1-(2-pyridinyl)-1H-1,2,4-triazol-3-yl]amino}benzoyl)-4-methoxybenzenesulphonohydrazide

[0143] Mass spectrum: ESI-MS: MH⁺=577

EXAMPLE 60N′-[3-({5-(2-Chlorophenyl)-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]benzenesulphonohydrazide

[0144] Mass spectrum: ESI-MS: MH⁺=614

[0145] The compounds of Examples 61 to 63 are obtained according to theprocess described in Example 1, using the appropriatesulphonohydrazides, isothiocyanates and hydrazines in Steps a, c and d,respectively, and in Step a replacing4-[(tert-butoxycarbonyl)amino]benzoic acid by4-{[(tert-butoxycarbonyl)amino]methyl}benzoic acid.

EXAMPLE 614-Methoxy-N′-{4-[({5-phenyl-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)methyl]benzoyl}benzenesulphonohydrazide

[0146] Mass spectrum: ESI-MS: MH⁺=737

EXAMPLE 62N′-(4-{[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]methyl}benzoyl)benzenesulphonohydrazide

[0147] Mass spectrum: ESI-MS: MH⁺=639

EXAMPLE 63N′-[4-({[5-Phenyl-1-(2-pyridinyl)-1H-1,2,4-triazol-3-yl]amino}methyl)benzoyl]benzenesulphonohydrazide

[0148] Mass spectrum: ESI-MS: MH⁺=754

[0149] The compounds of Examples 64 to 66 are obtained according to theprocess described in Example 1, using the appropriatesulphonohydrazides, isothiocyanates and hydrazines in Steps a, c and d,respectively, and in Step a replacing4-[(tert-butoxycarbonyl)amino]benzoic acid by{4-[(tert-butoxycarbonyl)amino]phenyl}acetic acid.

EXAMPLE 644-Methoxy-N′-{[4-({5-phenyl-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)phenyl]acetyl}benzenesulphonohydrazide

[0150] Mass spectrum: ESI-MS: MH⁺=623

EXAMPLE 65N′-({4-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]phenyl}acetyl)-4-methoxybenzenesulphonohydrazide

[0151] Mass spectrum: ESI-MS: MH⁺=555

EXAMPLE 664-Methoxy-N′-[(4-{[5-phenyl-1-(2-pyridinyl)-1H-1,2,4-triazol-3-yl]amino}phenyl)acetyl]benzenesulphonohydrazide

[0152] Mass spectrum: ESI-MS: MH⁺=556

[0153] The compounds of Examples 67 to 72 are obtained according to theprocess described in Example 1 using the appropriate sulphonohydrazides,isothiocyanates and hydrazines in Steps a, c and d, respectively, and inStep a replacing 4-[(tert-butoxycarbonyl)amino]benzoic acid by6-[(tert-butoxycarbonyl)amino]-3-pyridazinecarboxylic acid.

EXAMPLE 674-Methoxy-N′-{[6-({5-phenyl-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)-3-pyridazinyl]carbonyl}benzenesulphonohydrazide

[0154] Mass spectrum: ESI-MS: MH⁺=611

EXAMPLE 68N′-({6-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]-3-pyridazinyl}carbonyl)-4-methoxybenzenesulphonohydrazide

[0155] Mass spectrum: ESI-MS: MH⁺=543

EXAMPLE 694-Methoxy-N′-[(6-{[5-phenyl-1-(2-pyridinyl)-1H-1,2,4-triazol-3-yl]amino}-3-pyridazinyl)carbonyl]benzenesulphonohydrazide

[0156] Mass spectrum: ESI-MS: MH⁺=544

EXAMPLE 70N′-{[6-({5-Phenyl-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)-3-pyridazinyl]carbonyl}benzenesulphonohydrazide

[0157] Mass spectrum: ESI-MS: MH⁺=581

EXAMPLE 71N′-({6-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]-3-pyridazinyl}carbonyl)benzenesulphonohydrazide

[0158] Mass spectrum: ESI-MS: MH⁺=513

EXAMPLE 72N′-[(6-{[5-Phenyl-1-(2-pyridinyl)-1H-1,2,4-triazol-3-yl]amino}-3-pyridazinyl)carbonyl]benzenesulphonohydrazide

[0159] Mass spectrum: ESI-MS: MH⁺=514

[0160] The compounds of Examples 73 to 75 are obtained according to theprocess described in Example 1 using the appropriate sulphonohydrazides,isothiocyanates and hydrazines in Steps a, c and d, respectively, and inStep a replacing 4-[(tert-butoxycarbonyl)amino]benzoic acid by6-[(tert-butoxycarbonyl)amino]nicotinic acid.

EXAMPLE 73N′-{[6-({5-Phenyl-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)-3-pyridinyl]carbonyl}benzenesulphonohydrazide

[0161] Mass spectrum: ESI-MS: MH⁺=580

EXAMPLE 74N′-({6-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]-3-pyridinyl}carbonyl)benzenesulphonohydrazide

[0162] Mass spectrum: ESI-MS: MH⁺=512

EXAMPLE 75N′-[(6-{[5-Phenyl-1-(2-pyridinyl)-1H-1,2,4-triazol-3-yl]amino}-3-pyridinyl)carbonyl]benzenesulphonohydrazide

[0163] Mass spectrum: ESI-MS: MH⁺=513

[0164] The compounds of Examples 76 to 78 are obtained according to theprocess described in Example 1 using the appropriate sulphonohydrazidesand hydrazines.

EXAMPLE 764-Methyl-N′-[4-({5-oxo-1-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1H-1,2,4-triazol-3-yl}amino)benzoyl]benzenesulphonohydrazide

[0165] Mass spectrum: ESI-MS: MH⁺=533

EXAMPLE 772,4,6-Trimethyl-N′-[4-({5-oxo-1-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1H-1,2,4-triazol-3-yl}amino)benzoyl]benzenesulphonohydrazide

[0166] Mass spectrum: ESI-MS: MH⁺=561

EXAMPLE 78N′-[4-({5-Oxo-1-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1H-1,2,4-triazol-3-yl}amino)benzoyl]methanesulphonohydrazide

[0167] Mass spectrum: ESI-MS: MH⁺=457

EXAMPLE 79N′-[(6-{[5-Oxo-1-(2-pyridinyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl]amino}-3-pyridinyl)carbonyl]benzenesulphonohydrazide

[0168] The expected product is obtained according to the processdescribed in Example 1, Steps a, b and c, in Step a replacing4-[(tert-butoxycarbonyl)amino]benzoic acid by6-[(tert-butoxycarbonyl)amino]nicotinic acid, in Step c replacingbenzoyl isothiocyanate by ethyl thioxocarbamate, and, according to theprocess described in Example 21, Step b, replacing3-(trifluoromethyl)phenylhydrazine by 2-hydrazinopyridine.

[0169] Mass spectrum: ESI-MS: MH⁺=453

[0170] The products of Examples 80 to 96 are obtained according to theprocess described in Example 1, in Step a replacing thesulphonohydrazides by the appropriate hydrazides, and using theappropriate isothiocyanates and hydrazines in Steps c and d,respectively.

EXAMPLE 804-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]-N′-(3-nitrobenzoyl)benzohydrazide

[0171] Mass spectrum: ESI-MS: MH⁺=520

EXAMPLE 814-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]-N′-[4-(trifluoromethyl)benzoyl]benzohydrazide

[0172] Mass spectrum: ESI-MS: MH⁺=543

EXAMPLE 824-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]-N′-(3,4,5-trimethoxybenzoyl)benzohydrazide

[0173] Mass spectrum: ESI-MS: MH⁺=565

EXAMPLE 834-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]-N′-(3-methoxybenzoyl)benzohydrazide

[0174] Mass spectrum: ESI-MS: MH⁺=505

EXAMPLE 844-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]-N′-(4-methoxybenzoyl)benzohydrazide

[0175] Mass spectrum: ESI-MS: MH⁺=505

EXAMPLE 854-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]-N′-(3-furoyl)benzohydrazide

[0176] Mass spectrum: ESI-MS: MH⁺=465

EXAMPLE 864-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]-N′-isonicotinoylbenzohydrazide

[0177] Mass spectrum: ESI-MS: MH⁺=476

EXAMPLE 874-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]-N′-(1-naphthoyl)benzohydrazide

[0178] Mass spectrum: ESI-MS: MH⁺=539

EXAMPLE 88N′-(3,4-Dimethoxybenzoyl)-4-[(1,5-diphenyl-1H-1,2,4-triazol-3-yl)amino]benzohydrazide

[0179] Mass spectrum: ESI-MS: MH⁺=535

EXAMPLE 894-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]-N′-(2-naphthoyl)benzohydrazide

[0180] Mass spectrum: ESI-MS: MH⁺=525

EXAMPLE 90N′-(3-Chlorobenzoyl)-4-[(1,5-diphenyl-1H-1,2,4-triazol-3-yl)amino]benzohydrazide

[0181] Mass spectrum: ESI-MS: MH⁺=509

EXAMPLE 91N′-[3,5-Bis(trifluoromethyl)benzoyl]-4-[(1,5-diphenyl-1H-1,2,4-triazol-3-yl)amino]benzohydrazide

[0182] Mass spectrum: ESI-MS: MH⁺=611

EXAMPLE 924-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]-N′-(2-thienylcarbonyl)benzohydrazide

[0183] Mass spectrum: ESI-MS: MH⁺=481

EXAMPLE 93N′-(4-Chlorobenzoyl)-4-[(1,5-diphenyl-1H-1,2,4-triazol-3-yl)amino]benzohydrazide

[0184] Mass spectrum: ESI-MS: MH⁺=509

EXAMPLE 94N′-(2-Chlorobenzoyl)-4-[(1,5-diphenyl-1H-1,2,4-triazol-3-yl)amino]benzohydrazide

[0185] Mass spectrum: ESI-MS: MH⁺=509

EXAMPLE 954-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]-N′-(3-hydroxybenzoyl)benzohydrazide

[0186] Mass spectrum: ESI-MS: MH⁺=491

EXAMPLE 964-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]-N′-(3,4,5-trihydroxybenzoyl)benzohydrazide

[0187] Mass spectrum: ESI-MS: MH⁺=523

EXAMPLE 97N′-{4-[(1-Benzyl-3-phenyl-1H-1,2,4-triazol-5-yl)amino]benzoyl}benzenesulfonohydrazide

[0188] The title product isolated during the purification of thecompound described in example 15.

EXAMPLE 98N′-{4-[(1-Benzyl-3-phenyl-1H-1,2,4-triazol-5-yl)amino]benzoyl}-4-methoxybenzenesulfonohydrazide

[0189] The title product isolated during the purification of thecompound described in example 25.

PHARMACOLOGICAL STUDY Example A

[0190] Measurement of the Effect on Food Intake and Weight Developmentin the Obese Mouse

[0191] The compounds of the invention were administered in vivo to theobese ob/ob mouse in order to evaluate their influence on food intakeand weight development. The animals used are 13- to 18-week-old femaleob/ob C57B1/6J mice. They are divided into groups each comprising 4animals per cage, the cages being fitted with a grating floor, and themice having free access to food.

[0192] Before the experiments, the animals are conditioned for a periodranging from 2 to 3 weeks until their food consumption has stabilised.The experiments may be summarised as follows:

D-14 to D-7 conditioning

D-7 to D-3 measurement of the basal food intake

D0 to D + 3 animals treated twice daily, the control groups being giventhe carrier

D0 to D + 4 daily measurement of food intake and body weight.

[0193] The test compounds are dissolved, immediately before use, inwater, 0.9% sodium chloride, propylene glycol or dimethyl sulphoxide,depending upon their solubility, and are administered intraperitoneally(IP), in a volume of 2.5 ml/kg.

[0194] The parameters measured are the food intake and the body weight.

[0195] Results

[0196] The results are expressed as

[0197] percentage variation in food intake under treatment compared withthe basal food intake;

[0198] percentage variation in body weight between the first and lastday of treatment.

[0199] By way of example, the results obtained with the compounds ofExamples 1 and 6 are as follows: Food intake Body weight % variation(D1) % variation Product Dose (mg/kg) Control Treated (D4/D0) Example 11 −34 −45  −6.4 Example 6 5 −23 −34 −11.2

Example B

[0200] Meaurement of the in vitro Affinity for NPY Receptors

[0201] The capacity of the compounds of the invention to bind to NPYreceptors was measured on various cell lines, each expressing one of thereceptor sub-types studied. Competition binding experiments were carriedout using the peptide [¹²⁵I]-PYY as radioligand at concentrationsranging from 15 to 65 pM. The non-specific fraction is measured in thepresence of a concentration of 1 μM NPY. The cells are incubated for aperiod ranging from 1 to 2 hours depending upon the lines, and theradioactivity is collected after filtration over a GF/C filter treatedwith 0.1% PEI, before being measured.

[0202] Results

[0203] The results are expressed as IC₅₀. The compounds of the inventionappear to be capable of significantly displacing the reference ligand:the IC₅₀ values vary from a few nanomoles to some hundreds of nanomoles.

[0204] By way of example, the compounds of Examples 1 and 6 have an IC₅₀value of 80 nM and 7 nM, respectively, for the Y₅ receptor.

Example C

[0205] Acute Toxicity Study

[0206] Acute toxicity was evaluated after oral administration ofincreasing doses of the test compound to groups each comprising 8 mice(26±6 grams). The animals were observed at regular intervals over thecourse of the first day and daily for the two weeks following treatment.

[0207] The compounds of the invention appear to be not very toxic atall.

Example D

[0208] Pharmaceutical Composition

[0209] Formulation for the preparation of 1000 tablets each comprising adose of 10 mg Compound of Example 1 . . . 10 g Hydroxypropyl cellulose .. . 2 g Wheat starch . . . 10 g  Lactose . . . 100 g  Magnesium stearate. . . 3 g Talc . . . 3 g

We claim:
 1. A compound selected from those of formula (I):

wherein: n is 0 or 1, W represents —CO— or S(O)_(q) wherein q is 0, 1 or2, the grouping

 represents a group selected from:

Z represents alkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted arylalkyl, optionally substitutedarylalkenyl, optionally substituted arylalkynyl, optionally substitutedheteroarylalkenyl, optionally substituted heteroarylalkynyl oroptionally substituted heteroarylalkyl, A represents a grouping selectedfrom -A₂-, -A₁-A₂-, -A₂-A₁- and -A₁-A₂-A₁- wherein A₁ is alkylene and A₂represents optionally substituted phenylene, optionally substitutednaphthylene, cycloalkylene, or optionally substituted heteroarylene, Rrepresents hydrogen, alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted arylalkyl, optionallysubstituted arylalkenyl, optionally substituted arylalkynyl, optionallysubstituted heteroarylalkenyl, optionally substituted heteroarylalkynylor optionally substituted heteroarylalkyl, R₁ represents alkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted arylalkyl, optionally substituted arylalkenyl,optionally substituted arylalkynyl, optionally substitutedheteroarylalkenyl, optionally substituted heteroarylalkynyl oroptionally substituted heteroarylalkyl, their enantiomers,diastereoisomers, and addition salts thereof with apharmaceutically-acceptable acid or base, it being understood that theterm “alkyl” denotes a linear or branched group having from 1 to 6carbon atoms, the term “alkylene” denotes a linear or branched bivalentradical containing from 1 to 6 carbon atoms, the term alkenyl denotes alinear or branched group having from 2 to 6 carbon atoms and from 1 to 3double bond, the term alkynyl denotes a linear or branched group havingfrom 2 to 6 carbon atoms and from 1 to 3 triple bond, the term “aryl”denotes phenyl, naphthyl, biphenyl, dihydronaphthyl ortetrahydronaphthyl, the term “heteroaryl” denotes an unsaturated orpartially unsaturated mono- or bi-cyclic group having from 5 to 11 ringmembers, containing from 1 to 4 hetero atoms selected from nitrogen,oxygen and sulphur, the terms “phenylene” and “naphthylene” denotebivalent phenyl and naphthyl radicals, respectively, the termcycloalkylene denotes a bivalent saturated cyclic radical having from 3to 8 carbon atoms, the term “heteroarylene” denotes a bivalentheteroaryl radical as defined hereinbefore, the expression “optionallysubstituted” applied to the terms “aryl”, “arylalkyl”, “heteroaryl” or“heteroarylalkyl” means that those groups are substituted on theircyclic moiety by from 1 to 5 identical or different substituentsselected from linear or branched (C₁-C₆)alkyl, linear or branched(C₁-C₆)alkoxy, halogen, hydroxy, linear or branchedperhalo-(C₁-C₆)alkyl, nitro, amino (optionally substituted by one or twolinear or branched (C₁-C₆)alkyl), linear or branched (C₁-C₆)acyl,aminocarbonyl (optionally substituted on the nitrogen atom by one or twolinear or branched (C₁-C₆)alkyl), linear or branched (C₁-C₆)acylamino,linear or branched (C₁-C₆)alkoxycarbonyl, formyl, carboxy, sulpho,nitrile, linear or branched (C₁-C₆)aminoalkyl (optionally substituted onthe nitrogen atom by one or two linear or branched (C₁-C₆)alkyl), linearor branched (C₁-C₆)thioalkyl (optionally substituted on the sulfur atomby a linear or branched (C₁-C₆)alkyl), or linear or branched(C₁-C₆)hydroxyalkyl (optionally substituted on the oxygen atom by alinear or branched (C₁-C₆)alkyl), the expression “optionallysubstituted” applied to the terms “phenylene”, “naphthylene” or“heteroarylene” means that those groups are substituted by from one tothree identical or different groups selected from linear or branched(C₁-C₆)alkyl, linear or branched (C₁-C₆)alkoxy, halogen, hydroxy, linearor branched perhalo-(C₁-C₆)alkyl, nitro, amino (optionally substitutedby one or two linear or branched (C₁-C₆)alkyl), linear or branched(C₁-C₆)acyl, formyl, carboxy, linear or branched (C₁-C₆)alkoxycarbonyl,aminocarbonyl (optionally substituted on the nitrogen atom by one or twolinear or branched (C₁-C₆)alkyl), linear or branched (C₁-C₆)acylaminoand nitrile.
 2. Compounds of claim 1 wherein n is 1, their enantiomers,diastereoisomers and addition salts thereof with apharmaceutically-acceptable acid or base.
 3. Compounds of claim 1wherein n is 0, their enantiomers, diastereoisomers and addition saltsthereof with a pharmaceutically-acceptable acid or base.
 4. Compounds ofclaim 1 wherein W represents SO₂, their enantiomers, diastereoisomersand addition salts thereof with a pharmaceutically acceptable acid orbase.
 5. Compounds of claim 1 wherein the grouping

represents a group selected from:

their enantiomers, diastereoisomers and addition salts thereof with apharmaceutically-acceptable acid or base.
 6. Compounds of claim 1wherein the grouping

represents a group selected from:

their enantiomers, diastereoisomers and addition salts thereof with apharmaceutically-acceptable acid or base.
 7. Compounds of claim 1wherein A represents A₂, their enantiomers, diastereoisomers andaddition salts thereof with a pharmaceutically-acceptable acid or base.8. Compounds of formula (I) according to claim 1 wherein A represents-A₁-A₂- or -A₂-A₁-, their enantiomers, diastereoisomers and additionsalts thereof with a pharmaceutically-acceptable acid or base. 9.Compounds of claim 1 wherein R₁ represents optionally substituted aryl,their enantiomers, diastereoisomers and addition salts thereof with apharmaceutically-acceptable acid or base.
 10. Compounds of claim 1wherein R is selected from hydrogen, optionally substituted aryl andoptionally substituted heteroaryl, their enantiomers, diastereoisomersand addition salts thereof with a pharmaceutically-acceptable acid orbase.
 11. Compounds of claim 1 wherein Z represents a group selectedfrom alkyl, optionally substituted aryl, and optionally substitutedheteroaryl, their enantiomers, diastereoisomers and addition saltsthereof with a pharmaceutically acceptable acid or base.
 12. Compoundsof claim 1 wherein n is 1, W represents SO₂, A represents a groupselected from phenylene, pyridinylene and pyrazinylene, R₁ representsoptionally substituted aryl, R is selected from hydrogen, optionallysubstituted aryl and optionally substituted heteroaryl, and Z representsalkyl, optionally substituted aryl or optionally substituted heteroaryl,their enantiomers, diastereoisomers and addition salts thereof with apharmaceutically-acceptable acid or base.
 13. Compound of claim 1 whichisN′-[4-({5-phenyl-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]benzenesulphono-hydrazide.14. Compound of claim 1 which isN′-{4-[(5-phenyl-1H-1,2,4-triazol-3-yl)amino]benzoyl}benzenesulphonohydrazide.15. Compound of claim 1 which isN′-(4-{[5-phenyl-1-(2-pyridyl)-1H-1,2,4-triazol-3-yl]amino}benzoyl)benzenesulphonohydrazide.16. Compound of claim 1 which isN′-[4-({5-oxo-1-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1H-1,2,4-triazol-3-yl}amino)benzoyl}benzene-sulphonohydrazide.17. Compound of claim 1 which isN′-(4-{[5-oxo-1-(2-pyridyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl]amino}benzoyl)benzenesulphonohydrazide.18. Compound of claim 1 which isN′-[(6-{[5-oxo-1-(2-pyridinyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl]amino}-3-pyridinyl)carbonyl]benzene-sulphonohydrazide.19. A pharmaceutical composition useful as Neuropeptide Y receptorligand comprising as active principle an effective amount of a compoundas claimed in claim 1 together with one or morepharmaceutically-acceptable excipients or vehicles.
 20. A method fortreating a living body afflicted with a condition requiring aNeuropeptide Y receptor ligand selected from pathologies associated witheating behaviour disorders or energy balance disorders (such asdiabetes, obesity, bulimia, anorexia nervosa), arterial hypertension,anxiety, depression, epilepsy, sexual dysfunctions and sleep disorders,compridsing the step of administering to the living body an amount of acompound of claim 1 which is effective for alleviation of saidcondition.